Intracellular signaling of TypeII a receptor tyrosine phospatase

• Project/Area Number: 16H05139
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: Kadomatsu Kenji 名古屋大学, 医学系研究科, 教授 (80204519)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: コンドロイチン硫酸 / 受容体型チロシンフォスファターゼ / PTPRσ / コータクチン / オートファジー / 軸索再生 / 神経損傷 / 神経変性疾患 / 軸索 / 再生 / アクチン / チロシンフォスファターゼ / フォスファターゼ / 細胞内シグナル / 神経科学 / 糖鎖

Outline of Final Research Achievements

We identified the actin-binding protein cortactin as a substrate of protein tyrosine phosphatase σ (PTPRσ). PTPRσ was activated by chondroitin sulfate and dephosphorylated cortactin. As a consequence, the autophagy flux was disrupted at the step of autophagosome-lysosome fusion. In addition, we succeeded in comprehensive screening of PTPRσ substrates.
Our study provided solid evidence of the direct relationship between PTPR and autophagy. Considering that autophagy dysfunction is involved in various disorders such as neurodegenerative diseases, our results may influence a broad spectrum of research fields.

Academic Significance and Societal Importance of the Research Achievements

本研究は、PTPRとオートファジーの関連について直接のエビデンスを示す意味で重要である。加えて、これまで糖鎖は細胞表面で様々な分子と結合・相互作用することを主な役割とするという概念が定着しており、細胞内シグナルを動かすようなリガンド糖鎖の存在は予見されてはきたものの、それを示す直接のデータは乏しかった。本研究によってそれが示された意義は大きい。また、オートファジー不全はパーキンソン病やアルツハイマー病などの神経変性疾患で深く関与している。がんでもオートファジーと病態の関係が分かっている。これらを考え合わせると、本研究は多様な分野へ影響を与える基盤的研究となる。

Research Products

• [Journal Article] Generation and characterization of antagonistic anti-human interleukin (IL)-18 monoclonal antibodies with high affinity: Two types of monoclonal antibodies against full-length IL-18 and the neoepitope of inflammatory caspase-cleaved active IL-18. (2019)
  • Author(s): Nariai Y, Kamino H, Obayashi E, Kato H, Sakashita G, Sugiura T, Migita K, Koga T, Kawakami A, Sakamoto K, Kadomatsu K, Nakakido M, Tsumoto K, Urano T.
  • Journal Title: Archives of Biochemistry and Biophysics Volume: 663 Pages: 71-82
  • DOI: 10.1016/j.abb.2019.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Compositional analysis of the glycosaminoglycan family in velvet antlers of Sika deer (Cervus nippon) at different growing stages. (2019)
  • Author(s): Takeda-Okuda N, Mizumoto S, Zhang Z, Kim SK, Lee CH, Jeon BT, Hosaka YZ, Kadomatsu K, Yamada S, Tamura JI.
  • Journal Title: Glycoconj. J. Volume: 1 Issue: 2 Pages: 114-124
  • DOI: 10.1007/s10719-019-09859-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury. (2019)
  • Author(s): Funahashi Y, Kato N, Masuda T, Nishio F, Kitai H, Ishimoto T, Kosugi T, Tsuboi N, Matsuda N, Maruyama S, Kadomatsu K.
  • Journal Title: Lab. Invest. Volume: - Issue: 8 Pages: 1130-1142
  • DOI: 10.1038/s41374-019-0190-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GlcNAc6ST3 is a keratan sulfate sulfotransferase for the protein-tyrosine phosphatase PTPRZ in the adult brain (2019)
  • Author(s): Narentuya、Takeda-Uchimura Yoshiko、Foyez Tahmina、Zhang Zui、Akama Tomoya O.、Yagi Hirokazu、Kato Koichi、Komatsu Yukio、Kadomatsu Kenji、Uchimura Kenji
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 4387-4387
  • DOI: 10.1038/s41598-019-40901-2
  • Peer Reviewed / Open Access
• [Journal Article] Origin and initiation mechanisms of neuroblastoma. (2018)
  • Author(s): Tsubota S, Kadomatsu K.
  • Journal Title: Cell Tissue Res. Volume: 372 Issue: 2 Pages: 211-221
  • DOI: 10.1007/s00441-018-2796-z
  • NAID: 120006496408
  • Peer Reviewed
• [Journal Article] Lacking Ketohexokinase-A Exacerbates Renal Injury in Streptozotocin-induced Diabetic Mice. (2018)
  • Author(s): Tomohito Doke, Takuji Ishimoto, Takahiro Hayasaki, Satsuki Ikeda, Masako Hasebe, Akiyoshi Hirayama, Tomoyoshi Soga, Noritoshi Kato, Tomoki Kosugi, Naotake Tsuboi, Miguel A. Lanaspa, Richard J. Johnson, Kenji Kadomatsu, and Shoichi Maruyama
  • Journal Title: Metabolism Volume: 85 Pages: 161-170
  • DOI: 10.1016/j.metabol.2018.03.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases. (2018)
  • Author(s): Mori Y, Masuda T, Kosugi T, Yoshioka T, Hori M, Nagaya H, Maeda K, Sato Y, Kojima H, Kato N, Ishimoto T, Katsuno T, Yuzawa Y, Kadomatsu K, Maruyama S.
  • Journal Title: Clin Exp Nephrol. Volume: 22 Issue: 4 Pages: 815-824
  • DOI: 10.1007/s10157-017-1518-2
  • NAID: 120006529637
  • Peer Reviewed
• [Journal Article] Midkine Promotes Atherosclerotic Plaque Formation Through Its Pro-Inflammatory, Angiogenic and Anti-Apoptotic Functions in Apolipoprotein E-Knockout Mice (2018)
  • Author(s): Takemoto Y, Horiba M, Harada M, Sakamoto K, Takeshita K, Murohara T, Kadomatsu K, Kamiya K.
  • Journal Title: Circulation Journal Volume: 82 Issue: 1 Pages: 19-27
  • DOI: 10.1253/circj.CJ-17-0043
  • NAID: 130006281926
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Neuroblastoma stem cells and CFC1. (2017)
  • Author(s): Tsubota S, Kadomatsu K.
  • Journal Title: Oncotarget Volume: 8 Pages: 45032-45033
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of midkine in the development of pulmonary fibrosis (2017)
  • Author(s): Misa Kenichi、Tanino Yoshinori、Wang Xintao、Nikaido Takefumi、Kikuchi Masami、Sato Yuki、Togawa Ryuichi、Tanino Mishie、Tanaka Shinya、Kadomatsu Kenji、Munakata Mitsuru
  • Journal Title: Physiol Rep Volume: 5 Issue: 16 Pages: e13383-e13383
  • DOI: 10.14814/phy2.13383
  • Peer Reviewed / Open Access
• [Journal Article] Dual inhibition of P-glycoprotein and midkine may increase therapeutic effects of anticancer drugs. (2017)
  • Author(s): Aynacioglu AS, Bilir A, Kadomatsu K.
  • Journal Title: Med. Hypotheses Volume: 107 Pages: 26-28
  • DOI: 10.1016/j.mehy.2017.07.019
  • Peer Reviewed
• [Journal Article] Origin and mechanism of neuroblastoma. (2017)
  • Author(s): Tsubota S, Kadomatsu K.
  • Journal Title: Oncoscience Volume: 4 Issue: 7-8 Pages: 70-72
  • DOI: 10.18632/oncoscience.360
  • Peer Reviewed / Open Access
• [Journal Article] Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue. (2017)
  • Author(s): Scilabra SD, Yamamoto K, Pigoni M, Sakamoto K, Muller SA, Papadopoulou A, Lichtenthaler SF, Troeberg L, Nagase H, Kadomatsu K.
  • Journal Title: Matrix Biol. Volume: 59 Pages: 69-79
  • DOI: 10.1016/j.matbio.2016.07.004
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis. (2017)
  • Author(s): Masuda T, Maeda K, Sato W, Kosugi T, Sato Y, Kojima H, Kato N, Ishimoto T, Tsuboi N, Uchimura K, Yuzawa Y, Maruyama S, Kadomatsu K.
  • Journal Title: Am J Pathol. Volume: 187(4) Issue: 4 Pages: 740-751
  • DOI: 10.1016/j.ajpath.2016.12.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology. (2017)
  • Author(s): Zhang Z, Takeda-Uchimura Y, Foyez T, Ohtake-Niimi S, Narentuya, Akatsu H, Nishitsuji K, Michikawa M, Wyss-Coray T, Kadomatsu K, Uchimura K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114(14) Issue: 14 Pages: 114-114
  • DOI: 10.1073/pnas.1615036114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sulfatase 2 Modulates Fate Change from Motor Neurons to Oligodendrocyte Precursor Cells through Coordinated Regulation of Shh Signaling with Sulfatase 1 (2017)
  • Author(s): Jiang Wen、Ishino Yugo、Hashimoto Hirokazu、Keino-Masu Kazuko、Masu Masayuki、Uchimura Kenji、Kadomatsu Kenji、Yoshimura Takeshi、Ikenaka Kazuhiro
  • Journal Title: Developmental Neuroscience Volume: 39 Issue: 5 Pages: 361-374
  • DOI: 10.1159/000464284
  • Peer Reviewed
• [Journal Article] Differential involvement of vesicular and glial glutamate transporters around spinal α-motoneurons in the pathogenesis of SOD1G93A mouse model of amyotrophic lateral sclerosis (2017)
  • Author(s): Ohgomori Tomohiro、Yamasaki Ryo、Takeuchi Hideyuki、Kadomatsu Kenji、Kira Jun-ichi、Jinno Shozo
  • Journal Title: Neuroscience. Volume: 356 Pages: 114-124
  • DOI: 10.1016/j.neuroscience.2017.05.014
  • Peer Reviewed
• [Journal Article] A novel nuclear complex of DRR1, F-actin and COMMD1 involved in NF-κB degradation and cell growth suppression in neuroblastoma. (2017)
  • Author(s): Mu P, Akashi T, Lu F, Kishida S, Kadomatsu K.
  • Journal Title: Oncogene Volume: 36 Issue: 41 Pages: 5745-5756
  • DOI: 10.1038/onc.2017.181
  • Peer Reviewed
• [Journal Article] Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1 G93A mouse model of amyotrophic lateral sclerosis (2017)
  • Author(s): Ohgomori Tomohiro、Yamasaki Ryo、Takeuchi Hideyuki、Kadomatsu Kenji、Kira Jun-ichi、Jinno Shozo
  • Journal Title: Eur J Neurosci. Volume: 46 Issue: 4 Pages: 2001-2014
  • DOI: 10.1111/ejn.13650
  • Peer Reviewed / Open Access
• [Journal Article] Temporally and Spatially Regulated Expression of the Linker Histone H1fx During Mouse Development. (2017)
  • Author(s): Ichihara-Tanaka K, Kadomatsu K, Kishida S.
  • Journal Title: J Histochem Cytochem Volume: 65 Issue: 9 Pages: 513-530
  • DOI: 10.1369/0022155417723914
  • Peer Reviewed
• [Journal Article] PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma (2017)
  • Author(s): 2.Tsubota S, Kishida S, Shimamura T, Ohira M, Yamashita S, Cao D, Kiyonari S, Ushijima T, Kadomatsu K.
  • Journal Title: Cancer Res. Volume: 77 Issue: 19 Pages: 5259-5271
  • DOI: 10.1158/0008-5472.can-16-3144
  • Peer Reviewed
• [Journal Article] Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. (2017)
  • Author(s): 1.Su Z, Kishida S, Tsubota S, Sakamoto K, Cao D, Kiyonari S, Ohira M, Kamijo T, Narita A, Xu Y, Takahashi Y, Kadomatsu K.
  • Journal Title: Oncotarget Volume: 8 Issue: 63 Pages: 106296-106310
  • DOI: 10.18632/oncotarget.22435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mechanisms of axon regeneration: The significance of proteoglycans. (2017)
  • Author(s): Sakamoto K, Kadomatsu K.
  • Journal Title: Biochim Biophys Acta. Volume: 1861 Pages: 2435-2441
  • Peer Reviewed
• [Journal Article] Efficacy of urinary midkine as a biomarker in patients with acute kidney injury. (2016)
  • Author(s): Hayashi H, Sato W, Kosugi T, Nishimura K, Sugiyama D, Asano N, Ikematsu S, Komori K, Nishiwaki K, Kadomatsu K, Matsuo S, Maruyama S, Yuzawa Y.
  • Journal Title: Clin Exp Nephrol Volume: Epub Issue: 4 Pages: 597-607
  • DOI: 10.1007/s10157-016-1318-0
  • NAID: 120006623838
  • Peer Reviewed
• [Presentation] Midkine in atherosclerotic plaque formation ,Midkine promotes NFAT regulated T-cell activation & Th1 differentiation in lupus nephritis (2018)
  • Author(s): Kadomatsu, K.
  • Organizer: Fifth Midkine Symposium
  • Int'l Joint Research / Invited
• [Presentation] Proteoglycans in axon regeneration and neural plasticity. (2018)
  • Author(s): Kadomatsu, K.
  • Organizer: Iubm2018
  • Int'l Joint Research / Invited
• [Presentation] Glycans in Neural Plasticity (2017)
  • Author(s): Kadomatsu K.
  • Organizer: 2017 Glyco-retreat
  • Int'l Joint Research / Invited
• [Presentation] Glycosaminoglycans in axon regeneration and neural plasticity (2017)
  • Author(s): Kadomatsu K.
  • Organizer: 第1回 国際糖鎖神経シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Proteoglycans and neural plasticity (2017)
  • Author(s): Kadomatsu K.
  • Organizer: JCGG 日本糖鎖科学コンソーシアム
  • Int'l Joint Research / Invited
• [Remarks] 名古屋大学大学院医学系研究科生物化学講座分子生物学
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/basic-med/bio-chem/mol-biology/
• [Remarks] 名古屋大学大学院医学系研究科生物化学講座分子生物学
  • URL: https://www.med.nagoya-u.ac.jp/biochem/